Heterocyclo-alkylsulfonyl pyrazoles

ABSTRACT

The present invention relates to heterocyclo alkylsulfonyl pyrazoles of the formula I: 
                         
wherein the ring of the formula (R 5 )—A—(SO m R 4 ), m, X, R 1  through R 5  are as defined in the specification, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the invention are useful in the treatment or alleviation of inflammation and other inflammation associated disorders, such as arthritis, colon cancer, and Alzheimer&#39;s disease in mammals, preferably humans, dogs, cats and livestock animals.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims benefit from U.S. provisional application No.60/335,713, filed Nov. 2, 2001.

BACKGROUND OF THE INVENTION

This invention relates to heterocyclo-alkylsulfonyl pyrazoles, methodsof treatment and pharmaceutical compositions for the treatment ofcyclooxygenase mediated diseases, such as arthritis, neurodegenerationand colon cancer, in mammals, preferably humans, dogs, cats orlivestock.

Sulfonyl pyrazoles are useful in the treatment of cyclooxygenase (COX)mediated diseases, such as arthritis, neurodegeneration and coloncancer, in mammals, preferably humans, dogs, cats or livestock. Twoforms of COX are now known, a constitutive isoform (COX-1) and aninducible isoform (COX-2) of which expression is upregulated at sites ofinflammation (Vane, J. R.; Mitchell, et. al., Proc. Natl. Acad. Sci.USA, 1994, 91, 2046). COX-1 appears to play a physiological role and tobe responsible for gastrointestinal and renal protection. On the otherhand, COX-2 appears to play a pathological role and is believed to bethe predominant isoform present in inflammation conditions. Thetherapeutic use of conventional COX inhibitors are limited due to drugassociated side effects, including life threatening ulceration and renaltoxicity. Compounds that selectively inhibit COX-2 would exertanti-inflammatory effects without the adverse side effects associatedwith COX-1 inhibition. Preferred compounds of the invention areselective COX-2 inhibitors.

A variety of sulfonylpyrazoles that inhibit COX have been described inpatent publications WO 97/11704, WO 01/40216, EP 1104758, EP 1104759,and EP 1104760; U.S. Non-Provisional patent application Ser. No.09/798,752, filed 2 March, 2001; and U.S. Non-Provisional patentapplication Ser. No. 09/824,550, filed Apr. 2, 2001.

Filed simultaneously with the present application on Nov. 2, 2001, areU.S. Provisional Applications entitled “Hydrazinyl and Nitrogen OxidePyrazoles”; “5-Heteroatom-Substituted Pyrazoles”;“5-Heterocyclo-Pyrazoles”; and “5-(Alkylidene-Cycloalkyl)- and5-(Alkylidene-Heterocyclyl)-Pyrazoles”, which refer to certain pyrazoleCOX-2 inhibitors. The aforesaid applications are herein incorporated intheir entireties by reference.

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula I:

or the pharmaceutically acceptable salts thereof;wherein the ring of the formula (R⁵)—A—(SO_(m)R⁴) is selected from thegroup consisting of

m is 0, 1 or 2;

X is >CR⁵ or >N;

R¹ is a radical selected from the group consisting of H, —NO₂, —CN,(C₁–C₆)alkyl, (C₁–C₆)alkyl-SO₂—, (C₆–C₁₀)aryl-SO₂—, H—(C═O)—,(C₁–C₆)alkyl-(C═O)—, (C₁–C₆)alkyl-O—(C═O)—, (C₁–C₉)heteroaryl-(C═O)—,(C₁–C₉)heterocyclyl-(C═O)—, H₂N—(C═O)—, (C₁–C₆)alkyl-NH—(C═O)—,[(C₁–C₆)alkyl]₂—N—(C═O)—, [(C₆–C₁₀)aryl]—NH—(C═O)—,[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—, HO—NH—(C═O)—, and(C₁–C₆)alkyl-O—NH—(C═O)—;

R² is a radical selected from the group consisting of H, —NO₂, —CN,(C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₃–C₇)cycloalkyl, (C₆–C₁₀)aryl,(C₁–C₉)heteroaryl, (C₁–C₉)heterocyclyl, (C₁–C₆)alkyl-O—,(C₃–C₇)cycloalkyl-O—, (C₆–C₁₀)aryl-O—, (C₁–C₉)heteroaryl-O—,(C₁–C₉)heterocyclyl-O—, H—(C═O)—, (C₁–C₆)alkyl-(C═O)—,(C₃–C₇)cycloalkyl-(C═O)—, (C₆–C₁₀)aryl-(C═O)—, (C₁–C₉)heteroaryl-(C═O)—,(C₁–C₉)heterocyclyl-(C═O)—, (C₁–C₆)alkyl-O—(C═O)—,(C₃–C₇)cycloalkyl-O—(C═O)—, (C₆–C₁₀)aryl-O—(C═O)—,(C₁–C₉)heteroaryl-O—(C═O)—, (C₁–C₉)heterocyclyl-O—(C═O)—,(C₁–C₆)alkyl-(C═O)—O—, (C₃–C₇)cycloalkyl-(C═O)—O—,(C₆–C₁₀)aryl-(C═O)—O—, (C₁–C₉)heteroaryl-(C═O)—O—,(C₁–C₉)heterocyclyl-(C═O)—O—, (C₁–C₆)alkyl-(C═O)—NH—,(C₃–C₇)cycloalkyl-(C═O)—NH—, (C₆–C₁₀)aryl-(C═O)—NH—,(C₁–C₉)heteroaryl-(C═O)—NH—, (C₁–C₉)heterocyclyl-(C═O)—NH—,(C₁–C₆)alkyl-O—(C═O)—NH—, (C₁–C₆)alkyl-NH, [(C₁–C₆)alkyl]₂—N—,(C₃–C₇)cycloalkyl-NH—, [(C₃–C₇)cycloalkyl]₂—N—, [(C₆–C₁₀)aryl]—NH—,[(C₆–C₁₀)aryl]₂—N—, [(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—,[(C₁–C₉)heteroaryl]—NH—, [(C₁–C₉)heteroaryl]₂—N—,[(C₁–C₉)heterocyclyl]—NH—, [(C₁–C₉)heterocyclyl]₂—N—, H₂N—(C═O)—,HO—NH—(C═O)—, (C₁–C₆)alkyl-O—NH—(C═O)—, [(C₁–C₆)alkyl]—NH—(C═O)—,[(C₁–C₆)alkyl]₂—N—(C═O)—, [(C₃–C₇)cycloalkyl]—NH—(C═O)—,[(C₃–C₇)cycloalkyl]₂—N—(C═O)—, [(C₆–C₁₀)aryl]—NH—(C═O)—,[(C₆–C₁₀)aryl]₂—N—(C═O)—, [(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—,[(C₁–C₉)heteroaryl]—NH—(C═O)—, [(C₁–C₉)heteroaryl]₂—N—(C═O)—,[(C₁–C₉)heterocyclyl]—NH—(C═O)—, (C₁–C₆)alkyl-S— and (C₁–C₆)alkyloptionally substituted by one —OH substituent or by one to four fluorosubstituents;

R³ is a saturated (3- to 4-membered)-heterocyclyl ring radical; or asaturated, partially saturated or aromatic (7- to9-membered)-heterocyclyl ring radical;

wherein said saturated (3- to 4-membered)-heterocyclyl ring radical; orsaid saturated, partially saturated or aromatic (7- to9-membered)-heterocyclyl ring radical; may optionally contain one tofour ring heteroatoms independently selected from the groups consistingof —N═, —NH—, —O—, and —S—;

wherein said saturated (3- to 4-membered)-heterocyclyl ring radical; orsaid saturated, partially saturated or aromatic (7- to9-membered)-heterocyclyl ring radical; may optionally be substituted onany ring carbon atom by one to three substituents per ring independentlyselected from the group consisting of halo, —OH, —CN, —NO₂,(C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₃–C₇)cycloalkyl, (C₆–C₁₀)aryl,(C₂–C₉)heterocyclyl, (C₁–C₆)alkyl-O—, H—(C═O)—, (C₁–C₆)alkyl-(C═O)—,HO—(C═O)—, (C₁–C₆)alkyl-O—(C═O)—, —NH₂, (C₁–C₆)alkyl-NH—,[(C₁–C₆)alkyl]₂—N—, (C₃–C₇)cycloalkyl-NH—, (C₆–C₁₀)aryl-NH—,[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—, (C₁–C₉)heteroaryl-NH—, H₂N—(C═O)—,[(C₁–C₆)alkyl]—NH—(C═O)—, [(C₁–C₆)alkyl]₂—N—(C═O)—,[(C₆–C₁₀)aryl]—NH—(C═O)—, [(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—,(C₁–C₆)alkyl-O—NH—(C═O)—, (C₁–C₆)alkyl-(C═O)—HN—,(C₁–C₆)alkyl-(C═O)—[(C₁–C₆)alkyl-N]—, —SH, (C₁–C₆)alkyl-S—,(C₁–C₆)alkyl-(S═O)—, (C₁–C₆)alkyl-SO₂— and (C₁–C₆)alkyl optionallysubstituted with one to four fluoro moieties;

wherein said saturated (3- to 4-membered)-heterocyclyl ring radical; orsaid saturated, partially saturated or aromatic (7- to9-membered)-heterocyclyl ring radical; may also optionally besubstituted on any ring nitrogen atom by one to three substituents perring independently selected from the group consisting of(C₃–C₇)cycloalkyl, (C₆–C₁₀)aryl, (C₂–C₉)heterocyclyl, H—(C═O)—,(C₁–C₆)alkyl-(C═O)—, (C₁–C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,[(C₁–C₆)alkyl]—NH—(C═O)—, [(C₁–C₆)alkyl]₂—N—(C═O)—,[(C₆–C₁₀)aryl]—NH—(C═O)—, [(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—,(C₁–C₆)alkyl-O—NH—(C═O)—, and (C₁–C₆)alkyl optionally substituted withone to four fluoro moieties;

R⁴ is an (C₁–C₆)alkyl radical optionally substituted by one to fourfluoro substituents; and

R⁵ is a radical selected from the group consisting of H, halo, —OH,(C₁–C₆)alkyl-O—, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₃–C₇)cycloalkyl, —CN,H—(C═O)—, (C₁–C₆)alkyl-(C═O)—, (C₁–C₆)alkyl-(C═O)—O—, HO—(C═O)—,(C₁–C₆)alkyl-O—(C═O)—, (C₁–C₆)alkyl-NH—, [(C₁–C₆)alkyl]₂—N—,(C₃–C₇)cycloalkyl-NH—, (C₆–C₁₀)aryl-NH—,[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—, (C₁–C₉)heteroaryl-NH—, H₂N—(C═O)—,(C₁–C₆)alkyl-NH—(C═O)—, [(C₁–C₆)alkyl]₂—N—(C═O)—, (C₆–C₁₀)aryl-(C═O)—,[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—, (C₁–C₆)alkyl-O—NH—(C═O)—,(C₁–C₆)alkyl-S—, and (C₁–C₆)alkyl optionally substituted by one to fourfluoro substituents.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula I. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, acid citrate, tartrate, bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, para-toluenesulfonate and pamoate[i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula I. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula I that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cations(e.g., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine (meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The compounds of this invention include all stereoisomers (e.g., cis andtrans isomers) and all optical isomers of compounds of the formula I(e.g., R and S enantiomers), as well as racemic, diastereomeric andother mixtures of such isomers.

The compounds of the invention may also exist in different tautomericforms. This invention relates to all tautomers of formula I.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof.

Unless otherwise indicated, the term “functional group” refers to“radical”, “substituent” “moiety”, or “sub-moiety”, as defined below.The term “sub-functional group” refers to “substituent” “moiety”, or“sub-moiety”, as defined below.

Unless otherwise indicated, the term “radical” or “radicals” refers toan individual member of a variable (R¹, R², R³ etc) of the compound ofthe formula I (e.g., R¹ is a radical selected from the group consistingof H and (C₁–C₆)alkyl means that R¹ can be either a H radical or a(C₁–C₆)alkyl radical).

Unless otherwise indicated, the term “substituent” or “substituents”refers to a replacement of at least one atom of a radical, wherein theterm “radical” is as defined above, by another atom or group of atoms.For example, an (C₁–C₆)alkyl substituent may replace a hydrogen atom ofR¹ (C₆–C₁₀)aryl radical.

Unless otherwise indicated, the term “moiety” or “moieties” refers to areplacement of at least one atom of a substituent, wherein the term“substituent” is as defined above, by another atom or group of atoms.For example, an (C₁–C₆)alkyl moiety of a particular substituent (e.g.,(C₁–C₆)alkyl, (C₆–C₁₀)aryl, or (C₃–C₈)cycloalkyl substituent) mayreplace a hydrogen atom of that substituent.

Unless otherwise indicated, the term “sub-moiety” or “sub-moieties”refers to a replacement of at least one atom of a moiety, wherein theterm “moiety” is as defined above, by another atom or group of atoms.For example, an (C₁–C₆)alkyl sub-moiety of a particular moiety (e.g.,(C₁–C₆)alkyl, (C₆–C₁₀)aryl, or (C₃–C₈)cycloalkyl moiety) may replace ahydrogen atom of that moiety.

Unless otherwise indicated, the term “(C₁–C₆)alkyl” as well as the(C₁–C₆)alkyl component of other terms referred to herein (e.g., the(C₁–C₆)alkyl component of (C₁–C₆)alkyl-O—), may be linear or branched(such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,secondary-butyl, tertiary-butyl), wherein each of said (C₁–C₆)alkylfunctional group, wherever they occur, may optionally be substituted byone to three sub-functional groups per (C₁–C₆)alkyl componentindependently selected from the group consisting of fluoro, —OH,(C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₃–C₇)cycloalkyl, (C₁–C₆)alkyl-O—, oxo,H—(C═O)—, H₂N—(C═O)—, (C₁–C₆)alkyl-(C═O)—, —CN, —NO₂,(C₁–C₆)alkyl-O—(C═O)—, (C₁–C₆)alkyl-NH—, [(C₁–C₆)alkyl]₂—N—,(C₃–C₇)cycloalkyl-NH—, (C₆–C₁₀)aryl-NH—,[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—, (C₁–C₉)heteroaryl-NH—,(C₁–C₁₀)heterocyclyl-NH—, H₂N—(C═O)—, [(C₁–C₆)alkyl]—NH—(C═O)—,[(C₁–C₆)alkyl]₂—N—(C═O)—, [(C₆–C₁₀)aryl]—NH—(C═O)—,[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—, (C₁–C₆)alkyl-O—NH—(C═O)—,(C₆–C₁₀)aryl, (C₂–C₉)heteroaryl, (C₆–C₁₀)aryl-O—, (C₁–C₉)heteroaryl-O—,(C₁–C₉)heteroaryl-(C═O)—, (C₁–C₆)alkyl-S—, (C₁–C₆)alkyl-S(═O)—,(C₁–C₆)alkyl-SO₂—, (C₁–C₆)alkyl-(C═O)—NH—,(C₁–C₆)alkyl-(C═O)—NH—(C₁–C₆)alkyl-NH and (C₁–C₆)alkyl-(C═O)—O—.

Unless otherwise indicated, the term “halo” means fluoro, chloro, bromoor iodo.

Unless otherwise indicated, the term “(C₂–C₆)alkenyl” means straight orbranched hydrocarbon chain functional groups of 2 to 6 carbon atomshaving at least one double bond including, but not limited to ethenyl,1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, or 2-butenyl.

Unless otherwise indicated, the term “(C₂–C₆)alkynyl” is used herein tomean straight or branched hydrocarbon chain functional groups of 2 to 6carbon atoms having one triple bond including, but not limited to,ethynyl (—C≡C—H), propynyl (—CH₂—C≡C—H or —C≡C—CH₃), or butynyl(—CH₂—CH₂—C≡C—H, or —CH₂—C≡C—CH₃, or —C≡C—CH₂CH₃).

Unless otherwise indicated, the term “(C₃–C₇)cycloalkyl” refers to amono or bicyclic carbocyclic ring functional groups including, but notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, bicyclo[2.1]heptanyl,bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl; wherein said(C₃–C₇)cycloalkyl may optionally contain 1 or 2 double bonds including,but not limited to, cyclopentenyl, cyclohexenyl and cycloheptenyl.

Unless otherwise indicated, the term “(C₆–C₁₀)aryl” means aromaticfunctional groups such as phenyl, naphthyl, tetrahydronaphthyl, orindanyl, wherein said (C₆–C₁₀)aryl is optionally substituted on any ringcarbon atom by one to two sub-functional groups per ring, wherein saidsub-functional groups are independently selected from the groupconsisting of halo, —OH, —CN, —SH, HO—(C═O)—, —NO₂, (C₁–C₆)alkyl,(C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₃–C₇)cycloalkyl, (C₆–C₁₀)aryl,(C₁–C₉)heteroaryl, (C₁–C₉)heterocyclyl, (C₁–C₆)alkyl-O—, —OCF₃,(C₁–C₆)alkyl-S—, (C₁–C₆)alkyl-NH—, [(C₁–C₆)alkyl]₂—N—,(C₃–C₇)cycloalkyl-NH—, (C₆–C₁₀)aryl-NH—,[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—, (C₁–C₉)heteroaryl-NH—,(C₁–C₁₀)heterocyclyl-NH—, H₂N—(C═O)—, [(C₁–C₆)alkyl]—NH—(C═O)—,[(C₁–C₆)alkyl]₂—N—(C═O)—, [(C₆–C₁₀)aryl]—NH—(C═O)—,[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—, (C₁–C₆)alkyl-O—NH—(C═O)—,(C₁–C₆)alkyl-(C═O)—O—, (C₁–C₆)alkyl-(C═O)—NH—(C₁–C₆)alkyl-(C═O)—HN—(C₁–C₆)alkyl-NH, H—(C═O)—, (C₁–C₆)alkyl-(C═O)— and(C₁–C₆)alkyl-O—(C═O)—.

Unless otherwise indicated, the term “saturated, partially saturated oraromatic (7- to 9-membered)heterocyclyl” means a monocyclic saturated,partially saturated (7- to 9-membered)heterocyclic ring or bicyclicaromatic (7- to 9-membered)heterocyclic ring covalently bound to thepyrazole nucleus. Examples of the monocyclic saturated or partiallysaturated (7- to 9-membered)heterocyclic ring systems are azepanyl,diazepanyl, azocanyl, and the like. Examples of the bicyclic aromaticring systems are indolizin-4-yl-, indol-1-yl, isoindol-2-yl,3H-indol-1-yl, indolin-1-yl, benzo[b]furan-1-yl, benzo[b]thiophen-1-yl,1H-indazol-1-yl, 1H-indazol-2-yl, benzimidazol-1-yl, benzimidazol-3-yl,benzthiazol-1-yl, purin-1-yl, purin-3-yl, purin-7-yl, purin-9-yl and thelike. Examples of the bicyclic saturated or partially saturated (7- to9-membered)heterocyclic ring systems are quinuclidinyl,7-azabicyclo[2.2.1]heptanyl, aza-bicyclo[3.2.1]octyl,2,4,6-trithia-3a,7a-diazaindenyl and the like.

Unless otherwise indicated, the term “saturated (3- to4-membered)heterocyclyl” means a monocyclic (3- to4-membered)heterocyclic ring covalently bound to the pyrazole nucleus.Said ring may contain optional double bonds so as to include saturated(3- to 4-membered)-heterocyclic rings. Examples of the monocyclicsaturated or partially saturated ring systems are oxiranyl, azetidinyland aziridinyl and the like.

Unless otherwise indicated, the term“[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—” has the following structure:

wherein the term “(C₁–C₆)alkyl” and the term “(C₆–C₁₀)aryl” are asdefined above.

Unless otherwise indicated, the term“[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—” has the following structure:

wherein the term “(C₁–C₆)alkyl” and the term “(C₆–C₁₀)aryl” are asdefined above.

Unless otherwise indicated, the term“(C₁–C₆)alkyl-(C═O)—HN—(C₁–C₆)alkyl-NH” has the following structure:

wherein the term “(C₁–C₆)alkyl” is as defined above.

Unless otherwise indicated, the term “oxo” refers to ═O.

Unless otherwise indicated, the term “(C₁–C₉)heteroaryl” refers toaromatic or multicyclic functional groups wherein at least one ring ofthe functional groups is aromatic, wherein said aromatic or multicyclicfunctional groups contain one or more heteroatoms selected from thegroup consisting of O, S and N. The (C₁–C₉)heteroaryl functional groupscan be optionally substituted by one or more oxo sub-functional groups.Examples of heteroaryl functional groups include, but are not limitedto, benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl,benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl,benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl,imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl,triazinyl and triazolyl, wherein said (C₁–C₁₀)heteroaryl is optionallysubstituted on any atoms capable of forming an additional bond by one ortwo sub-functional groups independently selected from halo, —CN, —OH,(C₁–C₆)alkyl, perfluoro(C₁–C₆)alkyl, perfluoro(C₁–C₆)alkyl-O—,(C₁–C₆)alkyl-O— and (C₃–C₈)cycloalkyl-O—. Unless otherwise indicated,the foregoing (C₁–C₉)heteroaryls can be C-attached or N-attached wheresuch is possible. For instance, pyrrolyl can be pyrrol-1-yl (N-attached)or pyrrol-3-yl (C-attached).

Unless otherwise indicated, the term “(C₁–C₉)heterocyclyl” refers to acyclic functional groups containing 1 to 9 carbon atoms and 1 to 4heteroatoms selected from the group consisting of N, O and S. Theheterocyclyl ring can be optionally substituted where such is possibleby oxo, —CN, —OH, (C₁–C₆)alkyl, perfluoro(C₁–C₆)alkyl,perfluoro(C₁–C₆)alkyl-O—, (C₁–C₆)alkyl-O— and (C₃–C₈)cycloalkyl-O—.Examples of the cyclic functional groups include, but not limited to,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]-heptanyl, azetidinyl,dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl,1,3-dioxolanyl, 1,4-dithianyl, hexahydroazepinyl, hexahydropyrimidine,imidazolidinyl, imidazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl,piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl,pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, quinolizinyl,tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl,tetrahydrothienyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl ortrithianyl. Unless otherwise indicated, the foregoing heterocyclylfunctional groups can be C-attached or N-attached where such ispossible. For example, piperidinyl can be piperidin-1-yl (N-attached) orpiperidin-4-yl (C-attached).

In one embodiment of the present invention, R³ is saturated (7- to9-membered)-heterocyclyl ring radical containing one to four ringheteroatoms independently selected from the groups consisting of —N═,—NH—, —O—, and —S—.

In another embodiment of the present invention, R³ is partiallysaturated (7- to 9-membered)-heterocyclyl ring radical containing one tofour ring heteroatoms independently selected from the groups consistingof —N═, —NH—, —O—, and —S—.

In another embodiment of the present invention, R³ is aromatic (7- to9-membered)-heterocyclyl ring radical containing one to four ringheteroatoms independently selected from the groups consisting of —N═,—NH—, —O—, and —S—.

In another embodiment of the present invention, R³ is saturated,partially saturated or aromatic (7- to 9-membered)-heterocyclyl ringradical containing one to four ring heteroatoms independently selectedfrom the groups consisting of —N═, —NH—, —O—, and —S—; substituted onany ring carbon atom by one to three substituents per ring independentlyselected from the group consisting of halo, —OH, —CN, —NO₂, and(C₁–C₆)alkyl optionally substituted with one to four fluorosubstituents; preferably (C₁–C₆)alkyl optionally substituted with one tofour fluoro substituents; more preferably unsubstituted methyl orunsubstituted ethyl.

In another embodiment of the present invention, R³ is saturated,partially saturated or aromatic (7- to 9-membered)-heterocyclyl ringradical containing one to four ring heteroatoms independently selectedfrom the groups consisting of —N═, —NH—, —O—, and —S—; substituted onany ring carbon atom by one to three substituents per ring independentlyselected from the group consisting of (C₂–C₆)alkenyl, (C₂–C₆)alkynyl,(C₃–C₇)cycloalkyl, (C₆–C₁₀)aryl, and (C₂–C₉)heterocyclyl.

In another embodiment of the present invention, R³ is saturated,partially saturated or aromatic (7- to 9-membered)-heterocyclyl ringradical containing one to four ring heteroatoms independently selectedfrom the groups consisting of —N═, —NH—, —O—, and —S—; substituted onany ring carbon atom by one to three substituents per ring independentlyselected from the group consisting of (C₁–C₆)alkyl-O—, H—(C═O)—,(C₁–C₆)alkyl-(C═O)—, HO—(C═O)—, and (C₁–C₆)alkyl-O—(C═O)—.

In another embodiment of the present invention, R³ is saturated,partially saturated or aromatic (7- to 9-membered)-heterocyclyl ringradical containing one to four ring heteroatoms independently selectedfrom the groups consisting of —N═, —NH—, —O—, and —S—; substituted onany ring carbon atom by one to three substituents per ring independentlyselected from the group consisting of —NH₂, (C₁–C₆)alkyl-NH—,[(C₁–C₆)alkyl]₂—N—, (C₃–C₇)cycloalkyl-NH—, (C₆–C₁₀)aryl-NH—,[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—, and (C₁–C₉)heteroaryl-NH—.

In another embodiment of the present invention, R³ is saturated,partially saturated or aromatic (7- to 9-membered)-heterocyclyl ringradical containing one to four ring heteroatoms independently selectedfrom the groups consisting of —N═, —NH—, —O—, and —S—; substituted onany ring carbon atom by one to three substituents per ring independentlyselected from the group consisting of H₂N—(C═O)—,[(C₁–C₆)alkyl]—NH—(C═O)—, [(C₁–C₆)alkyl]₂—N—(C═O)—,[(C₆–C₁₀)aryl]—NH—(C═O)—, [(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—,(C₁–C₆)alkyl-O—NH—(C═O)—, (C₁–C₆)alkyl-(C═O)—HN—, and(C₁–C₆)alkyl-(C═O)-[(C₁–C₆)alkyl-N]—.

In another embodiment of the present invention, R³ is saturated,partially saturated or aromatic (7- to 9-membered)-heterocyclyl ringradical containing one to four ring heteroatoms independently selectedfrom the groups consisting of —N═, —NH—, —O—, and —S—; substituted onany ring carbon atom by one to three substituents per ring independentlyselected from the group consisting of —SH, (C₁–C₆)alkyl-S—,(C₁–C₆)alkyl-(S═O)—, and (C₁–C₆)alkyl-SO₂—.

In another embodiment of the present invention, R³ is saturated,partially saturated or aromatic (7- to 9-membered)-heterocyclyl ringradical containing one to four ring heteroatoms independently selectedfrom the groups consisting of —N═, —NH—, —O—, and —S—; substituted onany ring nitrogen atom by one to three substituents; preferably by onesubstituent; per ring independently selected from the group consistingof (C₃–C₇)cycloalkyl, (C₆–C₁₀)aryl, (C₂–C₉)heterocyclyl, and(C₁–C₆)alkyl optionally substituted with one to four fluoro moieties.

In another embodiment of the present invention, R is saturated,partially saturated or aromatic (7- to 9-membered)-heterocyclyl ringradical containing one to four ring heteroatoms independently selectedfrom the groups consisting of —N═, —NH—, —O—, and —S—; substituted onany ring nitrogen atom by one to three substituents per ringindependently selected from the group consisting of H—(C═O)—,(C₁–C₆)alkyl-(C═O)—, (C₁–C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,[(C₁–C₆)alkyl]—NH—(C═O)—, [(C₁–C₆)alkyl]₂—N—(C═O)—,[(C₆–C₁₀)aryl]—NH—(C═O)—, [(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—, and(C₁–C₆)alkyl-O—NH—(C═O)—; preferably selected from the group consistingof H—(C═O)— and (C₁–C₆)alkyl-(C═O)—; more preferably methyl-(C═O)—.

In another embodiment of the present invention, R³ is saturated,partially saturated or aromatic (7- to 9-membered)-heterocyclyl ringradical selected from the group consisting of optionally substitutedazepanyl, diazepanyl, azocanyl, and aza-bicyclo[3.2.1]octyl; preferablyR³ is azepan-1-yl or 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl.

In another embodiment of the present invention, R³ is saturated,partially saturated or aromatic (7- to 9-membered)-heterocyclyl ringradical unsubstituted by any substituents.

In another embodiment of the present invention, R³ is saturated (3- to4-membered)-heterocyclyl ring radical containing one to four ringheteroatoms independently selected from the groups consisting of —N═,—NH—, —O—, and —S—.

In another embodiment of the present invention, R³ is saturated (3- to4-membered)-heterocyclyl ring radical containing one to four ringheteroatoms independently selected from the groups consisting of —N═,—NH—, —O—, and —S—; substituted on any ring carbon atom by one to threesubstituents per ring independently selected from the group consistingof halo, —OH, —CN, —NO₂, and (C₁–C₆)alkyl optionally substituted withone to four fluoro moieties.

In another embodiment of the present invention, R³ is saturated (3- to4-membered)-heterocyclyl ring radical containing one to four ringheteroatoms independently selected from the groups consisting of —N═,—NH—, —O—, and —S—; substituted on any ring carbon atom by one to threesubstituents per ring independently selected from the group consistingof (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₃–C₇)cycloalkyl, (C₆–C₁₀)aryl, and(C₂–C₉)heterocyclyl.

In another embodiment of the present invention, R³ is saturated (3- to4-membered)-heterocyclyl ring radical containing one to four ringheteroatoms independently selected from the groups consisting of —N═,—NH—, —O—, and —S—; substituted on any ring carbon atom by one to threesubstituents per ring independently selected from the group consistingof (C₁–C₆)alkyl-O—, H—(C═O)—, (C₁–C₆)alkyl-(C═O)—, HO—(C═O)—, and(C₁–C₆)alkyl-O—(C═O)—.

In another embodiment of the present invention, R³ is saturated (3- to4-membered)-heterocyclyl ring radical containing one to four ringheteroatoms independently selected from the groups consisting of —N═,—NH—, —O—, and —S—; substituted on any ring carbon atom by one to threesubstituents per ring independently selected from the group consistingof —NH₂, (C₁–C₆)alkyl-NH—, [(C₁–C₆)alkyl]₂—N—, (C₃–C₇)cycloalkyl-NH—,(C₆–C₁₀)aryl-NH—, [(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—, and(C₁–C₉)heteroaryl-NH—.

In another embodiment of the present invention, R³ is saturated (3- to4-membered)-heterocyclyl ring radical containing one to four ringheteroatoms independently selected from the groups consisting of —N═,—NH—, —O—, and —S—; substituted on any ring carbon atom by one to threesubstituents per ring independently selected from the group consistingof H₂N—(C═O)—, [(C₁–C₆)alkyl]—NH—(C═O)—, [(C₁–C₆)alkyl]₂—N—(C═O)—,[(C₆–C₁₀)aryl]—NH—(C═O)—, [(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—,(C₁–C₆)alkyl-O—NH—(C═O)—, (C₁–C₆)alkyl-(C═O)—HN—, and(C₁–C₆)alkyl-(C═O)-[(C₁–C₆)alkyl-N]—.

In another embodiment of the present invention, R³ is saturated (3- to4-membered)-heterocyclyl ring radical containing one to four ringheteroatoms independently selected from the groups consisting of —N═,—NH—, —O—, and —S—; substituted on any ring carbon atom by one to threesubstituents per ring independently selected from the group consistingof —SH, (C₁–C₆)alkyl-S—, (C₁–C₆)alkyl-(S═O)—, and (C₁–C₆)alkyl-SO₂—.

In another embodiment of the present invention, R³ is saturated (3- to4-membered)-heterocyclyl ring radical containing one to four ringheteroatoms independently selected from the groups consisting of —N═,—NH—, —O—, and —S—; substituted on any ring nitrogen atom by one tothree substituents per ring independently selected from the groupconsisting of (C₃–C₇)cycloalkyl, (C₆–C₁₀)aryl, (C₂–C₉)heterocyclyl, and(C₁–C₆)alkyl optionally substituted with one to four fluoro moieties.

In another embodiment of the present invention, R³ is saturated (3- to4-membered)-heterocyclyl ring radical containing one to four ringheteroatoms independently selected from the groups consisting of —N═,—NH—, —O—, and —S—; substituted on any ring nitrogen atom by one tothree substituents per ring independently selected from the groupconsisting of H—(C═O)—, (C₁–C₆)alkyl-(C═O)—, (C₁–C₆)alkyl-O—(C═O)—,H₂N—(C═O)—, [(C₁–C₆)alkyl]—NH—(C═O)—, [(C₁–C₆)alkyl]₂—N—(C═O)—,[(C₆–C₁₀)aryl]—NH—(C═O)—, [(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—, and(C₁–C₆)alkyl-O—NH—(C═O)—.

In another embodiment of the present invention, R³ is saturated (3- to4-membered)-heterocyclyl ring radical selected from the group consistingof optionally substituted oxiranyl and aziridinyl; preferably R³ isoptionally substituted aziridinyl.

In another embodiment of the present invention, R³ is saturated (3- to4-membered)-heterocyclyl ring radical; or said saturated, partiallysaturated or aromatic (7- to 9-membered)-heterocyclyl ring radical;unsubstituted by any substituents.

In a preferred embodiment of the present invention, R⁴ is methyl orethyl radical optionally substituted by one to three fluoro atoms.

In a more preferred embodiment of the present invention, R⁴ is methyl,difluoromethyl, or trifluoromethyl.

In another embodiment of any of the foregoing embodiments of theinvention, the ring of the formula (R⁵)—A—(SO_(m)R⁴) is of the formula

preferably A2; wherein X is >CR⁵; wherein R⁵ is preferably H, and m is0, 1 or 2, preferably m is 2.

In another embodiment of any of the foregoing embodiments of theinvention, the ring of the formula (R⁵)—A—(SO_(m)R⁴) is of the formula

wherein m is 0, 1 or 2, preferably m is 2.

In another embodiment of any of the foregoing embodiments of theinvention, R¹ is a radical selected from the group consisting of H,—NO₂, and —CN, preferably R¹ is —CN.

In another embodiment of any of the foregoing embodiments of theinvention, R¹ is a radical selected from the group consisting ofH—(C═O)—, (C₁–C₆)alkyl-(C═O)—, (C₁–C₆)alkyl-O—(C═O)—,(C₁–C₉)heteroaryl-(C═O)—, and (C₁–C₉)heterocyclyl-(C═O)—.

In another embodiment of any of the foregoing embodiments of theinvention, R¹ is a radical selected from the group consisting ofH₂N—(C═O)—, (C₁–C₆)alkyl-NH—(C═O)—, [(C₁–C₆)alkyl]₂—N—(C═O)—,[(C₆–C₁₀)aryl]—NH—(C═O)—, [(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—,HO—NH—(C═O)—, and (C₁–C₆)alkyl-O—NH—(C═O)—.

In another embodiment of the present invention, R¹ is a radical selectedfrom the group consisting of —NO₂, —CN, (C₁–C₆)alkyl, (C₁–C₆)alkyl-SO₂—,(C₁–C₆)alkyl-(C═O)—, (C₁–C₆)alkyl-O—(C═O)—, and[(C₁–C₆)alkyl]₂—N—(C═O)—.

In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of(C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₃–C₇)cycloalkyl, (C₆–C₁₀)aryl,(C₁–C₉)heteroaryl, and (C₁–C₉)heterocyclyl.

In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of(C₁–C₆)alkyl-O—, (C₃–C₇)cycloalkyl-O—, (C₆–C₁₀)aryl-O—,(C₁–C₉)heteroaryl-O—, and (C₁–C₉)heterocyclyl-O—.

In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting ofH—(C═O)—, (C₁–C₆)alkyl-(C═O)—, (C₃–C₇)cycloalkyl-(C═O)—,(C₆–C₁₀)aryl-(C═O)—, (C₁–C₉)heteroaryl-(C═O)—, and(C₁–C₉)heterocyclyl-(C═O)—.

In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of(C₁–C₆)alkyl-O—(C═O)—, (C₃–C₇)cycloalkyl-O—(C═O)—,(C₆–C₁₀)aryl-O—(C═O)—, (C₁–C₉)heteroaryl-O—(C═O)— and(C₁–C₉)heterocyclyl-O—(C═O)—.

In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of(C₁–C₆)alkyl-(C═O)—O—, (C₃–C₇)cycloalkyl-(C═O)—O—,(C₆–C₁₀)aryl-(C═O)—O—, (C₁–C₉)heteroaryl-(C═O)—O—, and(C₁–C₉)heterocyclyl-(C═O)—O—.

In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of(C₁–C₆)alkyl-(C═O)—NH—, (C₃–C₇)cycloalkyl-(C═O)—NH—,(C₆–C₁₀)aryl-(C═O)—NH—, (C₁–C₉)heteroaryl-(C═O)—NH—,(C₁–C₉)heterocyclyl-(C═O)—NH—, and (C₁–C₆)alkyl-O—(C═O)—NH—.

In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of[(C₁–C₆)alkyl]₂—N—, (C₃–C₇)cycloalkyl-NH—, [(C₃–C₇)cycloalkyl]₂—N—,[(C₆–C₁₀)aryl]—NH—, [(C₆–C₁₀)aryl]₂—N—,[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—, [(C₁–C₉)heteroaryl]—NH—,[(C₁–C₉)heteroaryl]₂—N—, [(C₁–C₉)heterocyclyl]—NH—, and[(C₁–C₉)heterocyclyl]₂—N—.

In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting ofH₂N—(C═O)—, HO—NH—(C═O)—, and (C₁–C₆)alkyl-O—NH—(C═O)—.

In another embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of[(C₁–C₆)alkyl]—NH—(C═O)—, [(C₁–C₆)alkyl]₂—N—(C═O)—,[(C₃–C₇)cycloalkyl]—NH—(C═O)—, [(C₃–C₇)cycloalkyl]₂—N—(C═O)—,[(C₆–C₁₀)aryl]—NH—(C═O)—, [(C₆–C₁₀)aryl]₂—N—(C═O)—,[(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—, [(C₁–C₉)heteroaryl]—NH—(C═O)—,[(C₁–C₉)heteroaryl]₂—N—(C═O)—, [(C₁–C₉)heterocyclyl]—NH—(C═O)—, and(C₁–C₆)alkyl-S—.

In a preferred embodiment of any of the foregoing embodiments of theinvention, R² is a radical selected from the group consisting of H,—NO₂, —CN, or (C₁–C₆)alkyl optionally substituted by one —OH or by oneto four fluoro substituents; preferably R² is (C₁–C₆)alkyl optionallysubstituted by one —OH or by one to four fluoro substituents; morepreferably R² is —CF₃ or —CHF₂.

In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is a radical selected from the group consisting of H, haloand —CN.

In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is a radical selected from the group consisting of —OH and(C₁–C₆)alkyl-O—.

In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is a radical selected from the group consisting of(C₂–C₆)alkenyl and (C₂–C₆)alkynyl.

In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is (C₃–C₇)cycloalkyl.

In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is a radical selected from the group consisting ofH—(C═O)—, (C₁–C₆)alkyl-(C═O)—, (C₁–C₆)alkyl-(C═O)—O—, HO—(C═O)—, and(C₁–C₆)alkyl-O—(C═O)—.

In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is a radical selected from the group consisting of(C₁–C₆)alkyl-NH—, [(C₁–C₆)alkyl]₂—N—, (C₃–C₇)cycloalkyl-NH—,(C₆–C₁₀)aryl-NH—, [(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—, and(C₁–C₉)heteroaryl-NH—.

In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is a radical selected from the group consisting ofH₂N—(C═O)—, (C₁–C₆)alkyl-NH—(C═O)—, [(C₁–C₆)alkyl]₂—N—(C═O)—,(C₆–C₁₀)aryl-(C═O)—, [(C₁–C₆)alkyl]-[((C₆–C₁₀)aryl)—N]—(C═O)—, and(C₁–C₆)alkyl-O—NH—(C═O)—.

In another embodiment of any of the foregoing embodiments of theinvention, R⁵ is (C₁–C₆)alkyl-S—.

In a preferred embodiment of the present invention, R⁵ is H.

Examples of specific preferred compounds of the formula I are selectedfrom the group consisting of:

5-Azepan-1-yl-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

1-(5-Methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-1H-pyrazole-4-carbonitrile;

5-Azepan-1-yl-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile;

5-Azocan-1-yl-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

5-Azocan-1-yl-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile;

5-[1,4]Diazepan-1-yl-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

5-(4-Acetyl-[1,4]diazepan-1-yl)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

1-(5-Methanesulfonyl-pyridin-2-yl)-5-(4-methyl-[1,4]diazepan-1-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-(4-methyl-[1,4]diazepan-1-yl)-1H-pyrazole-4-carbonitrile;

1-(5-Methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-5-(3,3,5-trimethyl-azepan-1-yl)-1H-pyrazole-4-carbonitrile;and

3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-(3,3,5-trimethyl-azepan-1-yl)-1H-pyrazole-4-carbonitrile;or

the pharmaceutically acceptable salts thereof.

The present invention also relates to a pharmaceutical composition forthe treatment of a condition selected from the group consisting ofarthritis (including osteoarthritis, degenerative joint disease,spondyloarthropathies, gouty arthritis, systemic lupus erythematosus,juvenile arthritis and rheumatoid arthritis), fever (including rheumaticfever and fever associated with influenza and other viral infections),common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease,Crohn's disease, emphysema, acute respiratory distress syndrome, asthma,bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease,organ transplant toxicity, cachexia, allergic reactions, allergiccontact hypersensitivity, cancer (such as solid tumor cancer includingcolon cancer, breast cancer, lung cancer and prostrate cancer;hematopoietic malignancies including leukemias and lymphomas; Hodgkin'sdisease; aplastic anemia, skin cancer and familiar adenomatouspolyposis), tissue ulceration, peptic ulcers, gastritis, regionalenteritis, ulcerative colitis, diverticulitis, recurrentgastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia,synovitis, gout, ankylosing spondylitis, restenosis, periodontaldisease, epidermolysis bullosa, osteoporosis, loosening of artificialjoint implants, atherosclerosis (including atherosclerotic plaquerupture), aortic aneurysm (including abdominal aortic aneurysm and brainaortic aneurysm), periarteritis nodosa, congestive heart failure,myocardial infarction, stroke, cerebral ischemia, head trauma, spinalcord injury, neuralgia, neuro-degenerative disorders (acute andchronic), autoimmune disorders, Huntington's disease, Parkinson'sdisease, migraine, depression, peripheral neuropathy, pain (includinglow back and neck pain, headache and toothache), gingivitis, cerebralamyloid angiopathy, nootropic or cognition enhancement, amyotrophiclateral sclerosis, multiple sclerosis, ocular angiogenesis, cornealinjury, macular degeneration, conjunctivitis, abnormal wound healing,muscle or joint sprains or strains, tendonitis, skin disorders (such aspsoriasis, eczema, scleroderma and dermatitis), myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes (including types I andII diabetes, diabetic retinopathy, neuropathy and nephropathy), tumorinvasion, tumor growth, tumor metastasis, corneal scarring, scleritis,immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats),sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis,sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease,Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoandiseases (such as malaria, giardia, coccidia), reproductive disorders(preferably in livestock) and septic shock (preferably arthritis, fever,common cold, pain and cancer) in a mammal, preferably a human, cat,livestock or a dog, comprising an amount of a compound of formula I or apharmaceutically acceptable salt thereof effective in such treatment anda pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition forthe treatment of a condition that can be treated by selectivelyinhibiting COX-2 in a mammal, preferably a human, cat, livestock or dog,comprising a COX-2 selective inhibiting effective amount of a compoundof formula I or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition forthe treatment of a condition selected from the group consisting ofinflammatory diseases such as arthritis (including osteoarthritis,degenerative joint disease, spondyloarthropathies, gouty arthritis,systemic lupus erythematosus, juvenile arthritis and rheumatoidarthritis), or fever (including rheumatic fever and fever associatedwith influenza).

The present invention also relates to a method for treating a conditionselected from the group consisting of arthritis (includingosteoarthritis, degenerative joint disease, spondyloarthropathies, goutyarthritis, systemic lupus erythematosus, juvenile arthritis andrheumatoid arthritis), fever (including rheumatic fever and feverassociated with influenza and other viral infections), common cold,dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn'sdisease, emphysema, acute respiratory distress syndrome, asthma,bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease,organ transplant toxicity, cachexia, allergic reactions, allergiccontact hypersensitivity, cancer (such as solid tumor cancer includingcolon cancer, breast cancer, lung cancer and prostrate cancer;hematopoietic malignancies including leukemias and lymphomas; Hodgkin'sdisease; aplastic anemia, skin cancer and familiar adenomatouspolyposis), tissue ulceration, peptic ulcers, gastritis, regionalenteritis, ulcerative colitis, diverticulitis, recurrentgastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia,synovitis, gout, ankylosing spondylitis, restenosis, periodontaldisease, epidermolysis bullosa, osteoporosis, loosening of artificialjoint implants, atherosclerosis (including atherosclerotic plaquerupture), aortic aneurysm (including abdominal aortic aneurysm and brainaortic aneurysm), periarteritis nodosa, congestive heart failure,myocardial infarction, stroke, cerebral ischemia, head trauma, spinalcord injury, neuralgia, neuro-degenerative disorders (acute andchronic), autoimmune disorders, Huntington's disease, Parkinson'sdisease, migraine, depression, peripheral neuropathy, pain (includinglow back and neck pain, headache and toothache), gingivitis, cerebralamyloid angiopathy, nootropic or cognition enhancement, amyotrophiclateral sclerosis, multiple sclerosis, ocular angiogenesis, cornealinjury, macular degeneration, conjunctivitis, abnormal wound healing,muscle or joint sprains or strains, tendonitis, skin disorders (such aspsoriasis, eczema, scleroderma and dermatitis), myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes (including types I andII diabetes, diabetic retinopathy, neuropathy and nephropathy), tumorinvasion, tumor growth, tumor metastasis, corneal scarring, scleritis,immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats),sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis,sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease,Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoandiseases (such as malaria, giardia, coccidia), reproductive disorders(preferably in livestock) and septic shock (preferably arthritis, fever,common cold, pain and cancer) in a mammal, preferably a human, cat,livestock or a dog, comprising administering to said mammal an amount ofa compound of formula I or a pharmaceutically acceptable salt thereofeffective in treating such a condition.

The present invention also relates to a method for treating a disorderor condition that can be treated by selectively inhibiting COX-2 in amammal, preferably a human, cat, livestock or a dog, comprisingadministering to a mammal requiring such treatment a COX-2 selectiveinhibiting effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

The present invention also relates to a method for treating a conditionselected from the group consisting of inflammatory diseases such asarthritis (including osteoarthritis, degenerative joint disease,spondyloarthropathies, gouty arthritis, systemic lupus erythematosus,juvenile arthritis and rheumatoid arthritis), or fever (includingrheumatic fever and fever associated with influenza).

The term “treating”, as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or one or more symptoms of such disorder orcondition. The term “treatment”, as used herein, refers to the act oftreating, as “treating” is defined immediately above.

The term “livestock animals” as used herein refers to domesticatedquadrupeds, which includes those being raised for meat and variousbyproducts, e.g., a bovine animal including cattle and other members ofthe genus Bos, a porcine animal including domestic swine and othermembers of the genus Sus, an ovine animal including sheep and othermembers of the genus Ovis, domestic goats and other members of the genusCapra; domesticated quadrupeds being raised for specialized tasks suchas use as a beast of burden, e.g., an equine animal including domestichorses and other members of the family Equidae, genus Equus, or forsearching and sentinel duty, e.g., a canine animal including domesticdogs and other members of the genus Canis; and domesticated quadrupedsbeing raised primarily for recreational purposes, e.g., members of Equusand Canis, as well as a feline animal including domestic cats and othermembers of the family Felidae, genus Felis.

The term “selective” as used herein, refers to COX-1/COX-2 IC₅₀inhibition ratio of 5 or greater as determined for one of the in vitro,in vivo, or ex vivo assays described on 36–40.

The term “Companion animals” as used herein refers to cats, dogs andhorses. As used herein, the term “dog(s)” denotes any member of thespecies Canis familiaris, of which there are a large number of differentbreeds. While laboratory determinations of biological activity may havebeen carried out using a particular breed, it is contemplated that theinhibitory compounds of the present invention will be found to be usefulfor treating pain and inflammation in any of these numerous breeds. Dogsrepresent a particularly preferred class of patients in that they arewell known as being very susceptible to chronic inflammatory processessuch as osteoarthritis and degenerative joint disease, which in dogsoften results from a variety of developmental diseases, e.g., hipdysplasia and osteochondrosis, as well as from traumatic injuries tojoints. Conventional NSAIDs, if used in canine therapy, have thepotential for serious adverse gastrointestinal reactions and otheradverse reactions including kidney and liver toxicity. Gastrointestinaleffects such as single or multiple ulcerations, including perforationand hemorrhage of the esophagus, stomach, duodenum or small and largeintestine, are usually debilitating, but can often be severe or evenfatal.

The term “treating reproductive disorders (preferably in livestock)” asused herein refers to the use of the COX-2 inhibitors of the inventionin mammals, preferably livestock animals (cattle, pigs, sheep, goats orhorses), during the estrus cycle to control the time of onset of estrusby blocking the uterine signal for lysis of the corpus luteum, i.e.F-series prostaglandins, then removing the inhibition when the onset ofestrus is desired. There are settings where it is useful to control orsynchronize the time of estrus, especially when artificial inseminationor embryo transfer are to be performed. Such use also includes enhancingthe rate of embryo survival in pregnant livestock animals. BlockingF-series prostaglandin release can have several beneficial actionsincluding reducing uterine contractions, enhancing uteroplacentalbloodflow, supporting recognition of pregnancy and postponing lysis ofthe corpus luteum at the time when estrus would have occurred had theanimal not become pregnant (around Day 21 of pregnancy). Such treatmentalso abrogates the effects of stress on reproduction. For examplereductions in fertility caused by excessive heat, negative energybalance and other stresses which have a COX-2 mediated component, asdoes abortion induced by stress such as heat, transportation,co-mingling, palpation, infection, etc. Such treatment is also useful tocontrol the time of parturition, which is accompanied by release ofF-series prostaglandins that lead to lysis of the corpus luteum.Inhibition of COX-2 would block the onset of premature labor inlivestock animals, allowing the offspring time to mature before birth.Also there are settings where controlling the time of parturition is auseful tool for management of pregnant animals.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in Formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Compounds of the presentinvention, prodrugs thereof and pharmaceutically acceptable salts ofsaid compounds or of said prodrugs which contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis invention. Certain isotopically-labelled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of Formula I of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

This invention also encompasses pharmaceutical compositions containingprodrugs of compounds of the formula I. This invention also encompassesmethods of treating disorders that can be treated by the selectiveinhibition of COX-2 comprising administering prodrugs of compounds ofthe formula I. Compounds of formula I having free amino, amido, hydroxy,carboxylic acid ester, sulfonamide or carboxylic groups (especiallyalkyl-S— and alkyl-(S═O)—) can be converted into prodrugs. Prodrugsinclude compounds wherein an amino acid residue, or a polypeptide chainof two or more (e.g., two, three or four) amino acid residues which arecovalently joined through peptide bonds to free amino, hydroxy orcarboxylic acid groups of compounds of formula I. The amino acidresidues include the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also include, 4-hydroxyproline,hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin,beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine,homoserine, ornithine and methionine sulfone. Prodrugs also includecompounds wherein carbonates, carbamates, amides and alkyl esters arecovalently bonded to the above substituents of formula I through thecarbonyl carbon prodrug sidechain. Prodrugs also include metabolicallylabile groups such as ethers, acetates, mercaptans and sulfoxides.

One of ordinary skill in the art will appreciate that the compounds ofthe invention are useful in treating a diverse array of diseases. One ofordinary skill in the art will also appreciate that when using thecompounds of the invention in the treatment of a specific disease thatthe compounds of the invention may be combined with various existingtherapeutic agents used for that disease.

For the treatment of rheumatoid arthritis, the compounds of theinvention may be combined with agents such as TNF-α, inhibitors such asanti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules(such as Enbrel®), low dose methotrexate, lefunimide,hydroxychloroquine, d-penicifamine, auranofin or parenteral or oralgold.

The compounds of the invention can also be used in combination withexisting therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as celecoxib androfecoxib, analgesics and intraarticular therapies such ascorticosteroids and hyaluronic acids such as hyalgan and synvisc.

This invention also relates to a method of or a pharmaceuticalcomposition for treating inflammatory processes and diseases comprisingadministering a compound of formula I of this invention or its salt to amammal including a human, cat, livestock or dog, wherein saidinflammatory processes and diseases are defined as above and saidinhibitory compound is used in combination with one or more othertherapeutically active agents under the following conditions:

A.) where a joint has become seriously inflammed as well as infected atthe same time by bacteria, fungi, protozoa and/or virus, said inhibitorycompound is administered in combination with one or more antibiotic,antifungal, antiprotozoal and/or antiviral therapeutic agents;

B.) where a multi-fold treatment of pain and inflammation is desired,said inhibitory compound is administered in combination with inhibitorsof other mediators of inflammation, comprising one or more membersindependently selected from the group consisting essentially of:

(1) NSAIDs;

(2) H₁-receptor antagonists;

(3) kinin-B₁- and B₂-receptor antagonists;

(4) prostaglandin inhibitors selected from the group consisting of PGD-,PGF- PGI₂- and PGE-receptor antagonists;

(5) thromboxane A₂ (TXA₂-) inhibitors;

(6) 5-, 12- and 15-lipoxygenase inhibitors;

(7) leukotriene LTC₄-, LTD₄/LTE₄- and LTB₄-inhibitors;

(8) PAF-receptor antagonists;

(9) gold in the form of an aurothio group together with one or morehydrophilic groups;

(10) immunosuppressive agents selected from the group consisting ofcyclosporine, azathioprine and methotrexate;

(11) anti-inflammatory glucocorticoids;

(12) penicillamine;

(13) hydroxychloroquine;

(14) anti-gout agents including colchicine; xanthine oxidase inhibitorsincluding allopurinol; and uricosuric agents selected from probenecid,sulfinpyrazone and benzbromarone;

C. where older mammals are being treated for disease conditions,syndromes and symptoms found in geriatric mammals, said inhibitorycompound is administered in combination with one or more membersindependently selected from the group consisting essentially of:

(1) cognitive therapeutics to counteract memory loss and impairment;

(2) anti-hypertensives and other cardiovascular drugs intended to offsetthe consequences of atherosclerosis, hypertension, myocardial ischemia,angina, congestive heart failure and myocardial infarction, selectedfrom the group consisting of:

a. diuretics;

b. vasodilators;

c. β-adrenergic receptor antagonists;

d. angiotensin-II converting enzyme inhibitors (ACE-inhibitors), aloneor optionally together with neutral endopeptidase inhibitors;

e. angiotensin II receptor antagonists;

f. renin inhibitors;

g. calcium channel blockers;

h. sympatholytic agents;

i. α₂-adrenergic agonists;

j. α-adrenergic receptor antagonists; and

k. HMG-CoA-reductase inhibitors (anti-hypercholesterolemics);

(3) antineoplastic agents selected from:

a. antimitotic drugs selected from:

i. vinca alkaloids selected from:

[1] vinblastine and

[2] vincristine;

(4) growth hormone secretagogues;

(5) strong analgesics;

(6) local and systemic anesthetics; and

(7) H₂-receptor antagonists, proton pump inhibitors and othergastroprotective agents.

The active ingredient of the present invention may be administered incombination with inhibitors of other mediators of inflammation,comprising one or more members selected from the group consistingessentially of the classes of such inhibitors and examples thereof whichinclude, matrix metalloproteinase inhibitors, aggrecanase inhibitors,TACE inhibitors, leucotriene receptor antagonists, IL-1 processing andrelease inhibitors, ILra, H₁-receptor antagonists; kinin-B₁- andB₂-receptor antagonists; prostaglandin inhibitors such as PGD-,PGF-PGI₂— and PGE-receptor antagonists; thromboxane A₂ (TXA2-)inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene LTC₄-,LTD₄/LTE₄- and LTB₄-inhibitors; PAF-receptor antagonists; gold in theform of an aurothio group together with various hydrophilic groups;immunosuppressive agents, e.g., cyclosporine, azathioprine andmethotrexate; anti-inflammatory glucocorticoids; penicillamine;hydroxychloroquine; anti-gout agents, e.g., colchicine, xanthine oxidaseinhibitors, e.g., allopurinol and uricosuric agents, e.g., probenecid,sulfinpyrazone and benzbromarone.

The compounds of the present invention may also be used in combinationwith anticancer agents such as endostatin and angiostatin or cytotoxicdrugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol,taxotere and alkaloids, such as vincristine and antimetabolites such asmethotrexate.

The compounds of the present invention may also be used in combinationwith anti-hypertensives and other cardiovascular drugs intended tooffset the consequences of atherosclerosis, including hypertension,myocardial ischemia including angina, congestive heart failure andmyocardial infarction, selected from vasodilators such as hydralazine,β-adrenergic receptor antagonists such as propranolol, calcium channelblockers such as nifedipine, α₂-adrenergic agonists such as clonidine,α-adrenergic receptor antagonists such as prazosin and HMG-CoA-reductaseinhibitors (anti-hypercholesterolemics) such as lovastatin oratorvastatin.

The active ingredient of the present invention may also be administeredin combination with one or more antibiotic, antifungal, antiprotozoal,antiviral or similar therapeutic agents.

The compounds of the present invention may also be used in combinationwith CNS agents such as antidepressants (such as sertraline),anti-Parkinsonian drugs (such as L-dopa, requip, mirapex, MAOBinhibitors such as selegine and rasagiline, comP inhibitors such asTasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,nicotine agonists, dopamine agonists and inhibitors of neuronal nitricoxide synthase) and anti-Alzheimer's drugs such as donepezil, tacrine,COX-2 inhibitors, propentofylline or metryfonate.

The compounds of the present invention may also be used in combinationwith osteoporosis agents such as roloxifene, lasofoxifene, droloxifeneor fosomax and immunosuppressant agents such as FK-506 and rapamycin.

The present invention also relates to the formulation of the activeagents of the present invention alone or with one or more othertherapeutic agents which are to form the intended combination, includingwherein said different drugs have varying half-lives, by creatingcontrolled-release forms of said drugs with different release timeswhich achieves relatively uniform dosing; or, in the case of non-humanpatients, a medicated feed dosage form in which said drugs used in thecombination are present together in admixture in said feed composition.There is further provided in accordance with the present inventionco-administration in which the combination of drugs is achieved by thesimultaneous administration of said drugs to be given in combination;including co-administration by means of different dosage forms androutes of administration; the use of combinations in accordance withdifferent but regular and continuous dosing schedules whereby desiredplasma levels of said drugs involved are maintained in the patient beingtreated, even though the individual drugs making up said combination arenot being administered to said patient simultaneously.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated, the ringof the formula (R⁵)—A—(SO_(m)R⁴), m, n, X, and R¹ through R⁶ in thereaction schemes and discussion that follow are as defined above.

Scheme 1 refers to the preparation of a compound of formula I.

Referring to Scheme 1, a compound of formula I (i.e., a compound of theformulae IA1–IA6, respectively):

can be prepared by reacting a compound of formula II, i.e., a compoundof formulae IIA1–IIA6, respectively:

wherein R⁶ is a leaving group, with a compound of the formula R³-H inthe presence of a fluoride containing salt and in the presence of asolvent.

Suitable leaving groups R⁶ of the compound of formula II include halo,such as fluoro, chloro, iodo, or bromo; (C₁–C₆)alkyl-SO₃—, such asCH₃—SO₃—, CF₃—SO₃—, or CF₃CF₂—SO₃—; (C₆–C₁₀)aryl-SO₃—, such astosyl-SO₃— or phenyl-SO₃—; (C₁–C₆)alkyl-SO₂—, such as CH₃—SO₂—; or(C₆–C₁₀)aryl-SO₂—, such as phenyl-SO₂—. Preferably, the leaving group R⁶is halo, such as chloro; or (C₁–C₆)alkyl-SO₃—, such as CF₃—SO₃—, orCF₃CF₂—SO₃—.

Suitable fluoride containing salts include a metal salt, such aslithium, sodium, potassium, cesium, magnesium, calcium, strontium andbarium. Other suitable fluoride salts include tetra(C₁–C₈)alkylammoniumfluoride, such as tetrabutylammonium fluoride; or(C₁–C₁₆)alkyltri(C₁–C₂)alkylammonium fluoride, such ascetyltrimethylammonium fluoride.

The aforesaid reaction can be performed used in thin the presence ofabout 0.05 to about 10 equivalents; more preferably about 0.05 to about5 equivalents; most preferably about 0.1 to about 2 equivalents; of thefluoride containing salts relative to the compound of formula 1.

Unless otherwise indicated, the term “equivalents” refers to the numberof moles of the fluoride containing salt relative to the number of molesof the compound of the formula 1.

Suitable solvents used in the aforesaid reaction include acetonitrile,dichloromethane, chloroform, tetrahydrofuran, dichloroethane,dimethylsulfoxide, dimethylformamide, dimethylacetamide, or acetone.

The aforesaid reaction can be performed at a temperature of about 10° C.to about 100° C., preferably about 20° C. to about 80° C. The aforesaidreaction can be performed for a period from about 2 hours to about 96hours, preferably from about 12 hours to about 48 hours.

In the aforesaid reaction, when the fluoride containing salt is a metalsalt such as potassium fluoride or cesium fluoride; preferred solventsinclude dimethylsulfoxide, dimethylformamide, dimethylacetamide,acetone, or acetonitrile. Preferably, the aforesaid reaction isperformed at a temperature of about 10° C. to about 30° C. Preferably,the aforesaid reaction is performed in the presence of about 0.05 toabout 5 equivalents of the fluoride containing salts relative to thecompound of formula I.

In the aforesaid reaction, when the fluoride containing salt istetra(C₁–C₈)alkylammonium fluoride or(C₁–C₁₆)alkyltri(C₁–C₂)alkylammonium fluoride; preferred solventsinclude acetonitrile, dichloromethane, chloroform, tetrahydrofuran, ordichloroethane. Preferably, the aforesaid reaction is performed at atemperature of about 20° C. to about 80° C. Preferably, the aforesaidreaction is performed in the presence of about 0.05 to about 10equivalents of the fluoride containing salts relative to the compound offormula I.

Scheme 2 illustrates methods of preparing compounds of the formula II,which are intermediates useful in preparing compounds of the formula Iin Scheme 1.

Referring to Scheme 2, a compound of the formula II wherein R⁶ is halocan be prepared by reacting a compound of the formula III with ahalogenating agent in a polar solvent. Suitable halogenating agentsinclude oxalyl chloride, POCl₃, POBr₃, SOCl₂ or PCl₅, preferably POCl₃.Suitable solvents include methylene chloride, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP),preferably methylene chloride. The aforesaid reaction is generallycarried out at a temperature from about 20° C. to about 140° C.,preferably at about the reflux temperature of the polar solvent,preferably when the solvent is methylene chloride, the temperature is55° C. The aforesaid reaction is generally carried out for a period fromabout 1 hour to about 48 hours, preferably about 2 hours to about 24hours.

A compound of the formula II wherein R⁶ contains a —SO₃—, such as(C₁–C₆)alkyl-SO₃— or (C₆–C₁₀)aryl-SO₃—, can be prepared by reacting acompound of the formula III with a sulfonylating agent in a polarsolvent. Suitable sulfonylating agents include trifluoromethanesulfonicanhydride, methanesulfonyl chloride, or methanesulfonyl anhydride,preferably methanesulfonyl chloride. Suitable solvents for the aforesaidreaction include methylene chloride, N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP),preferably methylene chloride. The aforesaid reaction is generallycarried out at a temperature from about −10° C. to about 25° C.,preferably at about 0° C. The aforesaid reaction is generally carriedout for a period from about 1 hour to about 48 hours.

A compound of the formula II wherein said R⁶ contains a —SO₂—, such as(C₁–C₆)alkyl-SO₂— or (C₆–C₁₀)aryl-SO₂—, can be prepared by reacting acompound of the formula II wherein R⁶ is halo or contains a —SO₃—, asdefined above, with a sulfonating agent in a polar solvent. Suitablesulfonating agents include NaSO₃CH₃ or NaSO₃(C₆–C₁₀)aryl. Other suitablesulfonating agents include NaS(C₁–C₆)alkyl, such as NaSCH₃, orNaS(C₆–C₁₀)aryl, such as NaS(C₆H₅), followed by an oxidizing agent, suchas OXONE®, metachloroperbenzoic acid, or hydrogen peroxide. Suitablesolvents for the aforesaid reaction include DMF, DMA, or DMSO,preferably DMSO. The aforesaid reaction is generally carried out at atemperature from about minus 10° C. to about 120° C., preferably atabout 100° C. The aforesaid reaction is generally carried out for aperiod from about 1 hour to about 48 hours, preferably about 4 hours toabout 24 hours.

Compounds of the formula III can be prepared by reacting a compound offormula IV, wherein the ring of the formula (R⁵)—A—(SO_(m)R⁴) is asdefined above, with a reagent of the formula

wherein R is (C₁–C₆)alkyl, such as methyl; in a suitable solvent underacidic, neutral or basic conditions. Preferably, the reagent is4,4,4-trifluoro-3-oxo-butyric acid methyl ester. Suitable solventsinclude methanol, ethanol, DMF, DMSO, water or a mixture thereof.Suitable acids include hydrochloric acid or trifluoroacetic acid.Suitable bases include sodium hydroxide, potassium hydroxide andpotassium carbonate. The aforesaid reaction is generally carried out ata temperature from about 0° C. to about 140° C., preferably at about 20°C. to about 100° C., most preferably at about 20° C. to about 100° C.The aforesaid reaction is generally carried out for a period from about1 hour to about 24 hours, preferably from about 6 hours to about 16hours.

The above reagents of formula R²—(C═O)—CH(R¹)—(C═O)—OR are commerciallyavailable or can be prepared according to the methods described in JerryMarch, “Advanced Organic Chemistry”, 4th edition, 1992, and referencescited therein.

Compounds of formula IV are commercially available or can be made bymethods well known to those of ordinary skill in the art or according toScheme 3. For example, compounds of formula IV can be prepared by themethod described in Vavrina, et al,. Collection Czechoslov. Chem.Commun., Vol. 37, 1721 (1972), which is incorporated herein byreference.

Scheme 3 refers to a preparation of a compound of the formula IV, whichare intermediates useful in preparing compounds of the formula II inScheme 2.

Referring to Scheme 3, a compound of the formula IV (i.e., a compound ofthe formulae IVA1–IVA6, respectively):

can be prepared by reacting a compound of the formula V (Le., a compoundof the formulae VA1–VA6, respectively):

wherein L² is a leaving group and m is 1 or 2, with hydrazine(preferably anhydrous hydrazine) in the presence of a polar solvent.Suitable leaving groups L² include halo, triflate, or methylsulfonyl,preferably halo, such as chloro and bromo. Suitable solvents includealcohol (such as ethanol, methanol, propanol or butanol), DMSO, DMF,DMA, or NMP, preferably alcohol, most preferably ethanol. This reactioncan be carried out at a temperature from about 0° C. to about 140° C.,preferably at about the reflux temperature of the solvent. This reactioncan be carried out for a period of from about 1 hour to about 36 hours,preferably from about 2 hours to about 24 hours. Preferably the productis isolated as a salt, such as a hydrobromide or hydrochloride salt. Thehydrochloride salt is preferred.

The compound of the formula IV wherein m is 0 can be prepared byreacting a compound of the formula VI (i.e., a compound of the formulaeVIA1–VIA6, respectively):

wherein L² is a leaving group, with hydrazine (preferably anhydroushydrazine) in the presence of a polar solvent, under the conditiondescribed in the aforesaid paragraph.

The compound of the formula V (i.e., a compound of the formulae VA1–VA6,respectively, as defined above) can be prepared by reacting a compoundof the formula VI (i.e., a compound of the formulae VIA1–VIA6,respectively, as defined above), wherein L² is a leaving group, with anoxidizing reagent in the presence of a solvent. Suitable oxidizingagents include meta-chloroperbenzoic acid, hydrogen peroxide, sodiumperborate, or OXONE®, preferably OXONE®. Suitable solvents or solventmixtures include methanol-water, dioxane-water, tetrahydrofuran-water,methylene chloride, or chloroform, preferably methanol-water ormethylene chloride. The aforesaid reaction can be carried out at atemperature from about 0° C. to about 60° C., preferably the temperaturemay range from about 20° C. to about 25° C. (i.e. room temperature). Theaforesaid reaction can be carried out for a period of from about 0.5hours to about 24 hours, preferably about 16 hours.

The compounds of the formula VI (i.e., a compound of the formulaeVIA1–VIA6, respectively, as defined above) can be prepared from acompound of formula VII (i.e., a compound of the formulae VIIA1–VIIA6,respectively):

wherein each of L¹ and L² independently is a leaving group, by reactingsaid compound of the formula VII with a sulfur reagent in the presenceor absence of a base in a polar solvent. Suitable leaving groups L¹include halo or methyl-SO₂—, preferably halo, such as bromo or iodo.Suitable leaving groups L² halo or methyl-SO₂—, preferably halo, such asbromo or iodo. Suitable sulfur reagents include (C₁–C₆)alkyl-SH,(C₁–C₆)alkyl-S—S—(C₁–C₆)alkyl, (C₁–C₆)alkyl-SO₃—, NaS-(C₁–C₆)alkyl orKS-(C₁–C₆)alkyl. Suitable bases include sodium hydroxide, triethylamine,alkyllithiums (such as n-butyllithium, sec-butyllithium andtert-butyllithium) and lithium diisopropylamide. Suitable solventsinclude dialkylethers (such as dimethylether), alcohol (such asmethanol, ethanol and tert-butanol), THF, benzene, toluene, xylene, DMF,DMSO, dioxane, 1,2-dimethoxyethane and a mixture of an alcohol andwater. The aforesaid reaction can be carried out at a temperature fromabout −78° C. to 200° C., preferably the temperature may range fromabout −78° C. to about 120° C. The aforesaid reaction can be carried outfor a period of from about 1 minute to about 24 hours.

Compounds of the formula VII (i.e., a compound of the formulaeVIIA1–VIIA6 respectively, as defined above) may be prepared by methodswell known to those of ordinary skill in the art (see for example, EP1104760).

Unless indicated otherwise, the pressure of each of the above reactionsis not critical. Generally, the reactions will be conducted at apressure of about one to about three atmospheres, preferably at ambientpressure (about one atmosphere).

Those skilled in the art will appreciate that the above schemes describegeneral methods for preparing the compounds of the invention. Specificcompounds of formula I may possess sensitive functional groups thatrequire protecting groups when prepared with the intermediatesdescribed. Examples of suitable protecting groups may be found in T. W.Greene and P. Wuts, Protecting Groups in Organic Synthesis, John Wiley &Sons, 2nd Edition, New York, 1991.

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula I which are also acidic in nature arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the herein described acidic compounds offormula I. These non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium, calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum product yields.

Method for Assessing Biological Activities:

The activity of the compounds of the formula I of the present inventionmay be demonstrated by the following assays.

Human In vitro Assays

Human Cell-Based COX-1 Assay

Human peripheral blood obtained from healthy volunteers can be dilutedto 1/10 volume with 3.8% sodium citrate solution. The platelet-richplasma immediately obtained can be washed with 0.14 M sodium chloridecontaining 12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA. Platelets can thenbe washed with platelet buffer (Hanks buffer (Ca free) containing 0.2%BSA and 20 mM Hepes). Finally, the human washed platelets (HWP) can besuspended in platelet buffer at the concentration of 2.85×10⁸ cells/mland stored at room temperature until use. The HWP suspension (70 μlaliquots, final 2.0×10⁷ cells/ml) can be placed in a 96-well U bottomplate and 10 μl aliquots of 12.6 mM calcium chloride added. Plateletscan be incubated with A23187 (final 10 μM, Sigma) with test compound(0.1–100 μM) dissolved in DMSO (final concentration; less than 0.01%) at37° C. for 15 minutes. The reaction can be stopped by addition of EDTA(final 7.7 mM) and TxB2 in the supernatant quantitated by using aradioimmunoassay kit (Amersham) according to the manufacturer'sprocedure.

Human Cell-Based COX-2 Assay

The human cell based COX-2 assay can be carried out as previouslydescribed (Moore et al., Inflam. Res., 45, 54, 1996). Confluent humanumbilical vein endothelial cells (HUVECs, Morinaga) in a 96-well flatbottom plate can be washed with 80 ml of RPMI1640 containing 2% FBS andincubated with hIL-1β (final concentration 300 U/ml, R & D Systems) at37° C. for 24 hours. After washing, the activated HUVECs can beincubateed with test compound (final concentration; 0.1 nm–1 μM)dissolved in DMSO (final concentration; less than 0.01%) at 37° C. for20 minutes and stimulated with A23187 (final concentration 30 mM) inHanks buffer containing 0.2% BSA, 20 mM Hepes at 37° C. for 15 minutes.6-Keto-PGF_(1α), stable metabolite of PGI2, in the supernatant can bequantitated by using a radioimmunoassay method (antibody; PreseptiveDiagnostics, SPA; Amersham).

Canine In Vitro Assays

The following canine cell based COX 1 and COX-2 assays have beenreported in Ricketts et al., Evaluation of Selective Inhibition ofCanine Cyclooxygenase 1 and 2 by Carprofen and Other NonsteroidalAnti-inflammatory Drugs, American Journal of Veterinary Research, 59(11), 1441–1446.

Protocol for Evaluation of Canine COX-1 Activity

Test drug compounds can be solubilized and diluted the day before theassay can be to be conducted with 0.1 mL of DMSO/9.9 mL of Hank'sbalanced salts solution (HBSS) and stored overnight at 4° C. On the daythat the assay can be carried out, citrated blood can be drawn from adonor dog, centrifuged at 190×g for 25 minutes at room temperature andthe resulting platelet-rich plasma can then be transferred to a new tubefor further procedures. The platelets can be washed by centrifuging at1500×g for 10 minutes at room temperature. The platelets can be washedwith platelet buffer comprising Hank's buffer (Ca free) with 0.2% bovineserum albumin (BSA) and 20 mM HEPES. The platelet samples can then beadjusted to 1.5×10⁷/mL, after which 50 μl of calcium ionophore (A23187)together with a calcium chloride solution can be added to 50 μl of testdrug compound dilution in plates to produce final concentrations of 1.7μM A23187 and 1.26 mM Ca. Then, 100 μl of canine washed platelets can beadded and the samples can be incubated at 37° C. for 15 minutes, afterwhich the reaction can be stopped by adding 20 μl of 77 mM EDTA. Theplates can then be centrifuged at 2000×g for 10 minutes at 4° C., afterwhich 50 μl of supernatant can be assayed for thromboxane B₂ (TXB₂) byenzyme-immunoassay (EIA). The pg/mL of TXB₂ can be calculated from thestandard line included on each plate, from which it can be possible tocalculate the percent inhibition of COX-1 and the IC₅₀ values for thetest drug compounds.

Protocol for Evaluation of Canine COX-2 Activity

A canine histocytoma (macrophage-like) cell line from the American TypeCulture Collection designated as DH82, can be used in setting up theprotocol for evaluating the COX-2 inhibition activity of various testdrug compounds. There can be added to flasks of these cells 10 μg/mL ofLPS, after which the flask cultures can be incubated overnight. The sametest drug compound dilutions as described above for the COX-1 protocolcan be used for the COX-2 assay and can be prepared the day before theassay can be carried out. The cells can be harvested from the cultureflasks by scraping and can then be washed with minimal Eagle's media(MEM) combined with 1% fetal bovine serum, centrifuged at 1500 rpm for 2minutes and adjusted to a concentration of 3.2×10⁵ cells/mL. To 50 μl oftest drug dilution there can be added 50 μl of arachidonic acid in MEMto give a 10 μM final concentration and there can be added as well 100μl of cell suspension to give a final concentration of 1.6×10⁵ cells/mL.The test sample suspensions can be incubated for 1 hour and thencentrifuged at 1000 rpm for 10 minutes at 4° C., after which 50 IIaliquots of each test drug sample can be delivered to EIA plates. TheEIA can be performed for prostaglandin E₂ (PGE₂) and the pg/mLconcentration of PGE₂ can be calculated from the standard line includedon each plate. From this data it can be possible to calculate thepercent inhibition of COX-2 and the IC₅₀ values for the test drugcompounds. Repeated investigations of COX-1 and COX-2 inhibition can beconducted over the course of several months. The results are averagedand a single COX-1 COX-2 ratio is calculated.

Whole blood assays for COX-1 and COX-2 are known in the art such as themethods described in C. Brideau, et al., A Human Whole Blood Assay forClinical Evaluation of Biochemical Efficacy of CyclooxygenaseInhibitors, Inflammation Research, Vol. 45, pp. 68–74 (1996). Thesemethods may be applied with feline, canine or human blood as needed.

In vivo Assays

Carrageenan Induced Foot Edema in Rats

Male Sprague-Dawley rats (5 weeks old, Charles River Japan) can befasted overnight. A line can be drawn using a marker above the ankle onthe right hind paw and the paw volume (V0) can be measured by waterdisplacement using a plethysmometer (Muromachi). Animals can be givenorally either vehicle (0.1% methyl cellulose or 5% Tween 80) or a testcompound (2.5 ml per 10 g body weight). One hour later, the animals canthen be injected intradermally with λ-carrageenan (0.1 ml of 1% w/vsuspension in saline, Zushikagaku) into right hind paw (Winter et al.,Proc. Soc. Exp. Biol. Med., 111, 544, 1962; Lombardino et al., Arzneim.Forsch., 25, 1629, 1975) and three hours later, the paw volume (V3) canbe measured and the increase in volume (V3−V0) calculated. Since maximuminhibition attainable with classical NSAIDs is 60–70%, ED₃₀ values canbe calculated.

Gastric Ulceration in Rats

The gastric ulcerogenicity of test compound can be assessed by amodification of the conventional method (Ezer et al., J. Pharm.Pharmacol., 28, 655, 1976; Cashin et al., J. Pharm. Pharmacol., 29,330–336, 1977). Male Sprague-Dawley rats (5 weeks old, Charles RiverJapan), fasted overnight, can be given orally either vehicle (0.1%methyl cellulose or 5% Tween 80) or a test compound (1 ml per 100 g bodyweight). Six hours after, the animals can be sacrificed by cervicaldislocation. The stomachs can be removed and inflated with 1% formalinsolution (10 ml). Stomachs can be opened by cutting along the greatercurvature. From the number of rats that showed at least one gastriculcer or haemorrhaging erosion (including ecchymosis), the incidence ofulceration can be calculated. Animals did not have access to either foodor water during the experiment.

Canine Whole Blood Ex Vivo Determinations of COX-1 and COX-2 ActivityInhibition

The in vivo inhibitory potency of a test compound against COX-1 andCOX-2 activity may be evaluated using an ex vivo procedure on caninewhole blood. Three dogs can be dosed with 5 mg/kg of the test compoundadministered by oral gavage in 0.5% methylcellulose vehicle and threedogs can be untreated. A zero-hour blood sample can be collected fromall dogs in the study prior to dosing, followed by 2- and 8-hourpost-dose blood sample collections. Test tubes can be preparedcontaining 2 μL of either (A) calcium ionophore A23187 giving a 50 μMfinal concentration, which stimulates the production of thromboxane B₂(TXB₂) for COX-1 activity determination; or of (B) lipopolysaccharide(LPS) to give a 10 μg/mL final concentration, which stimulates theproduction of prostaglandin E₂ (PGE₂) for COX-2 activity determination.Test tubes with unstimulated vehicle can be used as controls. A 500 μLsample of blood can be added to each of the above-described test tubes,after which they can be incubated at 37° C. for one hour in the case ofthe calcium ionophore-containing test tubes and overnight in the case ofthe LPS-containing test tubes. After incubation, 10 μL of EDTA can beadded to give a final concentration of 0.3%, in order to preventcoagulation of the plasma which sometimes occurs after thawing frozenplasma samples. The incubated samples can be centrifuged at 4° C. andthe resulting plasma sample of ˜200 μL can be collected and stored at−20° C. in polypropylene 96-well plates. In order to determine endpointsfor this study, enzyme immunoassay (EIA) kits available from Cayman canbe used to measure production of TXB₂ and PGE₂, utilizing the principleof competitive binding of tracer to antibody and endpoint determinationby colorimetry. Plasma samples can be diluted to approximate the rangeof standard amounts which would be supplied in a diagnostic or researchtools kit, i.e., 1/500 for TXB₂ and 1/750 for PGE₂.

The data set out in Table 1 below show how the percent inhibition ofCOX-1 and COX-2 activity is calculated based on their zero hour values.The data is expressed as treatment group averages in pg/ml of TXB₂ andPGE₂ produced per sample. Plasma dilution can be not factored in saiddata values.

The data in Table 1 show that, in this illustration, at the 5 mg/kg dosethere can be significant COX-2 inhibition at both timepoints. The datain Table 1 also show that at the 5 mg/kg dose there can be nosignificant inhibition of COX-1 activity at the timepoints involved.Accordingly, the data in Table 1 clearly demonstrates that at the 5mg/kg dosage concentration this compound possesses good COX-2selectivity.

TABLE 1 COX-1 ACTIVITY INHIBITION - Group Averages TXB₂ Pg/mL/WellPercent Inhibition Hour 0-hour 2-hour 8-hour 2-hour 8-hour Untreated  46 45 140  2%  0% 5 mg/kg  41  38 104  7%  0% COX-2 ACTIVITY INHIBITION -Group Averages PGE₂ Pg/mL/Well Percent Inhibition Hour 0-hour 2-hour8-hour 2-hour 8-hour Untreated 420 486 501  0%  0% 5 mg/kg 711 165 35077% 51%COX inhibition is observed when the measured percent inhibition isgreater than that measured for untreated controls. The percentinhibition in the above table is calculated in a straightforward mannerin accordance with the following equation:

${\%\mspace{14mu}{Inhibition}\mspace{14mu}\left( {2\text{-}{hour}} \right)} = \frac{\left( {{{PGE}_{2}\mspace{14mu} a\; t\mspace{20mu} t} = 0} \right) - \left( {{{PGE}_{2}\mspace{14mu} a\; t{\mspace{14mu}\;}t} = 2} \right)}{\left( {{{PGE}_{2}\mspace{14mu} a\; t{\mspace{14mu}\;}t} = 0} \right)}$Data Analysis

Statistical program packages, SYSTAT (SYSTAT, INC.) and StatView (AbacusCencepts, Inc.) for Macintosh can be used. Differences between testcompound treated group and control group can be tested for using ANOVA.The IC₅₀ (ED30) values can be calculated from the equation for thelog-linear regression line of concentration (dose) versus percentinhibition.

Most compounds prepared in the Working Examples as described hereinaftercan be tested by at least one of the methods described above and showedIC₅₀ values of 0.001 μM to 3 μM with respect to inhibition of COX-2 ineither the canine or human assays.

COX-2 selectivity can be determined by ratio in terms of IC₅₀ value ofCOX-1 inhibition to COX-2 inhibition. In general, it can be said that acompound showing a COX-1/COX-2 inhibition ratio of more than 5 has goodCOX-2 selectivity.

The compounds of the formula I of this invention can be administered viaoral, parenteral, anal, buccal or topical routes to mammals (includinghumans, dogs, cats, horses and livestock).

In general, these compounds are most desirably administered to humans indoses ranging from 0.01 mg to 100 mg per kg of body weight per day,although variations will necessarily occur depending upon the weight,sex and condition of the subject being treated, the disease state beingtreated and the particular route of administration chosen. However, adosage level that is in the range of from 0.1 mg to 10 mg per kg of bodyweight per day, single or divided dosage is most desirably employed inhumans for the treatment of above-mentioned diseases.

These compounds are most desirably administered to said non-humanmammals, e.g. dogs, cats, horses or livestock in an amount, expressed asmg per kg of body weight of said member per day, ranging from about 0.01mg/kg to about 20.0 mg/kg/day, preferably from about 0.1 mg/kg to about12.0 mg/kg/day, more preferably from about 0.5 mg/kg to about 10.0mg/kg/day and most preferably from about 0.5 mg/kg to about 8.0mg/kg/day.

The compounds of the present invention may be administered alone or incombination with pharmaceutically acceptable carriers or diluents byeither of the above routes previously indicated and such administrationcan be carried out in single or multiple doses. More particularly, thenovel therapeutic agents of the invention can be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, trochees, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrupsand the like. Such carriers include solid diluents or fillers, sterileaqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored.In general, the therapeutically-effective compounds of this inventionare present in such dosage forms at concentration levels ranging from 5%to 70% by weight, preferably 10% to 50% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate,dipotassium phosphate and glycine may be employed along with variousdisintegrants such as starch and preferably corn, potato or tapiocastarch, alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatine capsules; preferred materials in this connectionalso include lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various combinations thereof.

A preferred composition for dogs comprises an ingestible liquid peroraldosage form selected from the group consisting of a solution,suspension, emulsion, inverse emulsion, elixir, extract, tincture andconcentrate, optionally to be added to the drinking water of the dogbeing treated. Any of these liquid dosage forms, when formulated inaccordance with methods well known in the art, can either beadministered directly to the dog being treated, or may be added to thedrinking water of the dog being treated. The concentrate liquid form, onthe other hand, is formulated to be added first to a given amount ofwater, from which an aliquot amount may be withdrawn for administrationdirectly to the dog or addition to the drinking water of the dog.

A preferred composition provides delayed-, sustained- and/orcontrolled-release of said anti-inflammatory selective COX-2 inhibitor.Such preferred compositions include all such dosage forms which produce≧80% inhibition of COX-2 isozyme activity and result in a plasmaconcentration of said inhibitor of at least 3 fold the COX-2 IC₅₀ for atleast 4 hours; preferably for at least 8 hours; more preferably for atleast 12 hours; more preferably still for at least 16 hours; even morepreferably still for at least 20 hours; and most preferably for at least24 hours. Preferably, there is included within the above-describeddosage forms those which produce ≧80% inhibition of COX-2 isozymeactivity and result in a plasma concentration of said inhibitor of atleast 5 fold the COX-2 IC₅₀ for at least 4 hours, preferably for atleast 8 hours, more preferably for at least 12 hours, still morepreferably for at least 20 hours and most preferably for at least 24hours. More preferably, there is included the above-described dosageforms which produce ≧90% inhibition of COX-2 isozyme activity and resultin a plasma concentration of said inhibitor of at least 5 fold the COX-2IC₅₀ for at least 4 hours, preferably for at least 8 hours, morepreferably for at least 12 hours, still more preferably for at least 20hours and most preferably for at least 24 hours.

For parenteral administration, solutions of a compound of the presentinvention in either sesame or peanut oil or in aqueous propylene glycolmay be employed. The aqueous solutions should be suitably buffered(preferably pH>8) if necessary and the liquid diluent first renderedisotonic. These aqueous solutions are suitable for intravenous injectionpurposes. The oily solutions are suitable for intra-articular,intra-muscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well-known to those skilled in theart. Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of creams, jellies,gels, pastes, ointments and the like, in accordance with standardpharmaceutical practice.

The compounds of formula I may also be administered in the form ofsuppositories for rectal or vaginal administration of the activeingredient. These compositions can be prepared by mixing the activeingredient with a suitable non-irritating excipient which is solid atroom temperature (for example, 10° C. to 32° C.) but liquid at therectal temperature and will melt in the rectum or vagina to release theactive ingredient. Such materials are polyethylene glycols, cocoabutter, suppository and wax.

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

For transdermal administration, transdermal patches prepared inaccordance with well known drug delivery technology may be prepared andapplied to the skin of a mammal, preferably a human or a dog, to betreated, whereafter the active agent by reason of its formulatedsolubility characteristics migrates across the epidermis and into thedermal layers of the skin where it is taken up as part of the generalcirculation, ultimately providing systemic distribution of the activeingredient over a desired, extended period of time. Also included areimplants which are placed beneath the epidermal layer of the skin, i.e.between the epidermis and the dermis of the skin of the patient beingtreated. Such an implant will be formulated in accordance with wellknown principles and materials commonly used in this delivery technologyand may be prepared in such a way as to provide controlled-, sustained-and/or delayed-release of the active ingredient into the systemiccirculation of the patient. Such subepidermal (subcuticular) implantsprovide the same facility of installation and delivery efficiency astransdermal patches, but without the limitation of being subject todegradation, damage or accidental removal as a consequence of beingexposed on the top layer of the patient's skin.

EXAMPLES

The following examples contain detailed descriptions of the methods ofthe preparation of compounds of formula 1. These detailed descriptionsfall within the scope of the invention and serve to exemplify the abovedescribed general synthetic procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended to restrict the scope of the present invention.

The invention is illustrated in the following non-limiting examples inwhich, unless stated otherwise: all operations can be carried out atroom or ambient temperature, that is, in the range of 18–25° C.;evaporation of solvent was carried out using a rotary evaporator underreduced pressure with a bath of up to 60° C.; reactions were monitoredby thin layer chromatography (TLC) and analytical column liquidchromatography, and reaction times are given for illustration only;melting points (m.p.) given are uncorrected (polymorphism may result indifferent melting points); structure and purity of all isolatedcompounds were assured by at least one of the following techniques: TLC(Merck silica gel 60 F-254 precoated plates), high performance liquidchromatograpy (HPLC), or mass spectrometry. Flash column chromatographywas carried out using Merck silica gel 60 (230–400 mesh ASTM).Preparative HPLC was carried out using Hewlett Packard 1100 LiquidChromatography/Mass Selective Detector (LC/MSD). Separation was done ona Monochrom 5μ CN column PN 0509-250*212 from MetaChem Technologies. Theflow rate was 20 ml/min running a gradient of 0 to 90% of isopropanol inn-hexane. Low-resolution mass spectral data (EI) were obtained on anAutomass 120 (JEOL) mass spectrometer. Liquid Chromatography data wascollected on a Hewlett Packard 1100 Liquid Chromatography/Mass SelectiveDetector (LC/MSD). Analysis was performed on a Luna C-18 column withdimensions of 3.0×150 mm. The flow rate was 0.425 ml/minute running agradient of 50% 0.1% aqueous formic acid and 50% acetonitrile to 100%acetonitrile in 15 minutes. The ionization type for the mass detector ofthe Mass Spectrophotometer was atmospheric pressure electrospray in thepositive ion mode with a fragmentor voltage of 50 volts.

Example 15-Azepan-1-yl-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile

5-Chloro-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile(70 mg, 0.2 mmol) and triethylamine (40 mg, 0.4 mmol) were dissolved indry dichloroethane (1.5 ml) and potassium fluoride (0.35 mg, 0.6 mmol)was added to the solution. The mixture was stirred at 20° C. for aperiod of 48 hours. Analytical HPLC indicated the reaction completion.The mixture was purified directly by preparative TLC to provide thedesired product as white solid. MS: 414 (M+H); r.t.: 2.6 min.

The following compounds summarized in the following Table 2 may beprepared according to the procedure described in the above Example 1 byusing an appropriate starting material.

TABLE 2

I Ex.# A m R¹ R³ R⁴ R⁵ R⁶ 1 A2, wherein X is 2 CN CF₃ CH₃ Hazepan-1-yl >CH 2 A2, wherein X is 2 CN CF₃ CH₃ H1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl >CH 3 A2, wherein X is 2 CNCHF₂ CH₃ H azepan-1-yl >CH 4 A2, wherein X is 2 CN CF₃ CH₃ Hazocan-1-yl >CH 5 A2, wherein X is 2 CN CHF₂ CH₃ H azocan-1-yl >CH 6 A2,wherein X is 2 CN CF₃ CH₃ H [1,4]-diazepan-1-yl >CH 7 A2, wherein X is 2CN CF₃ CH₃ H 4-acetyl-[1,4]-diazepan-1-yl >CH 8 A2, wherein X is 2 CNCF₃ CH₃ H 4-methyl-[1,4]-diazepan-1-yl >CH 9 A2, wherein X is 2 CN CHF₂CH₃ H 4-methyl-[1,4]-diazepan-1-yl >CH 10  A2, wherein X is 2 CN CF₃ CH₃H 3,3,5-trimethyl-azepan-1-yl >CH 11  A2, wherein X is 2 CN CHF₂ CH₃ H3,3,5-trimethyl-azepan-1-yl >CH Referring to Table 2, Ex.#. refers toExample number;

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims that follow and that such claims be interpreted as broadly asis reasonable.

1. A compound wherein said compound is selected from the groupconsisting of:5-Azepan-1-yl-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;1-(5-Methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-1H-pyrazole-4-carbonitrile;5-Azepan-1-yl-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile;5-Azocan-1-yl-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;5-Azocan-1-yl-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile;5-[1,4]Diazepan-1-yl-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;5-(4-Acetyl-[1,4]diazepan-1-yl)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;1-(5-Methanesulfonyl-pyridin-2-yl)-5-(4-methyl-[1,4]diazepan-1-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-(4-methyl-[1,4]diazepan-1-yl)-1H-pyrazole-4-carbonitrile;1-(5-Methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-5-(3,3,5-trimethyl-azepan-1-yl)-1H-pyrazole-4-carbonitrile;and3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-(3,3,5-trimethyl-azepan-1-yl)-1H-pyrazole-4-carbonitrile;or a pharmaceutically acceptable salt thereof.